Osteoporosis, a chronic disease causing significant morbidity among an increasingly large population, is difficult to diagnose and treat. An important goal is prevention of osteoporosis, though its multi-factorial etiology has prevented elucidation of all its causes. Homocystinuria, an inborn error of metabolism resulting from deficient cystathionine beta- synthase activity, is characterized by elevated homocysteine levels in blood and early onset of severe osteoporosis of the spine and long bones. The probability of homocysteinemia, in the absence of a genetic disease, increases with age and after menopause and may result from several factors: nutrient deficiencies (vitamin B6 and folic acid), malabsorption (due to vitamin B12 deficiency, excess alcohol intake or non-steroidal anti-inflammatory drug use), a high methionine diet (i.e., a high animal protein diet) and/or unknown factors. Thus, it is our hypothesis that elevated levels of homocysteine represent another risk factor for osteoporosis. We shall investigate the effects of elevated homocysteine on bone cell growth, extracellular matrix synthesis, bone formation and bone resorption by using an in vitro approach. Rat bone marrow cells, under the appropriate culture conditions, can be induced to make bone or to produce active osteoclasts. We shall add exogenous homocysteine or cause the cells to produce elevated levels of homocysteine (by imposing nutrient deficiencies) and assay effects on the parameters named above. Thus, we shall be able to assess the effects of elevated homocysteine on the two components of bone homeostasis, formation and resorption, at functional levels. If data supporting our hypothesis are obtained, we shall undertake a cross-sectional study of plasma homocysteine levels in elderly people with and without osteoporosis and, ultimately, for an intervention trial in which dietary strategies are used to lower homocysteine levels.